ABSTRACT Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents in the United States. While generally very treatable, advanced RMS often proves resistant to treatment and results in poor survival. RMS is linked to a muscle lineage and is believed to result, at least in part, from a failure of the transcription factor MyoD to functionally promote terminal differentiation. Our laboratory has long studied the role of NF-?B as a regulator of skeletal muscle differentiation, and has shown that active NF-?B prevents the maturation of muscle, which is relevant in a number of diseases, including RMS. Because NF-?B is known to play an important role in the ability of a number of cancers to resist cell death, we examined whether NF-?B would have the same cell survival activity in RMS cells as a potential mechanism of chemoresistance. Interestingly, RMS cells depleted of NF-?B remained resistant to stress. This finding led us to uncover that RMS cells depend upon MyoD for cell survival. Further, we have determined that this MyoD-mediated resistance to cell death occurs through a novel transcriptional repressive function of MyoD. The goal of our project is to explore a potential new function of MyoD as a cell survival factor in the progression of RMS and unravel the manner in which MyoD is acting to repress gene transcription, potentially relevant to RMS pathogenesis. Because the current paradigm of future RMS treatments is to promote cell differentiation through stimulation of MyoD, our current findings paired with our proposed aims have the potential to alter future RMS therapies. !